NDT Advance Access originally published online on March 19, 2004
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Nephrol Dial Transplant (2004) 19: 1412-1419
Nephrol Dial Transplant Vol. 19 No. 6 © ERA-EDTA 2004; all rights reserved
Original Article
Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis
Department of Internal Medicine, Divisions of 1Clinical Immunology and 4Nephrology, 2Department of Pathology and Laboratory Medicine, University Hospital Groningen and 3Division of Vascular and Connective Tissue Research, TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands
Correspondence and offprint requests to: Jan-Stephan Sanders, MD, University Hospital Groningen, Department of Clinical Immunology, Hanzeplein 1, 9700 GZ Groningen, The Netherlands. Email: j.sanders{at}int.azg.nl
Background. Expression of matrix metalloproteinases (MMPs) by infiltrating and intrinsic renal cells is increased in inflammatory conditions, and may correlate with disease activity of glomerulonephritis. We analysed renal expression of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil and monocyte infiltration in renal biopsies of patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
Methods. Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and monocyte-derived MMP activators cathepsin G, neutrophil elastase and myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6) associated glomerulonephritis, and in normal renal tissue (n = 4). Double labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68, labelling neutrophils and macrophages.
Results. MMP-2-, MMP-3-, MMP-9- and TIMP-1-positive cells were detected in ANCA-associated glomerulonephritis in glomeruli with active inflammation (cellular crescents or fibrinoid necrosis), only occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue, no expression was detected, with the exception of weak mesangial staining for MMP-2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1 correlated with glomerular cathepsin G expression, while the number of MMP-9-expressing cells per glomerulus correlated with the percentage of crescentic glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1 expression correlated with renal function at the time of renal biopsy.
Conclusions. Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1 is increased in active ANCA-associated glomerulonephritis and correlates with inflammatory activity.
Keywords: ANCA-associated glomerulonephritis; enzyme inhibitors; extracellular matrix; immunohistochemistry; matrix metalloproteinases
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